EXCHANGE 


Some  New  Condensations  with  Para* 

para-bis  (Dimethylamino)-Benzo- 

hydrol  (Michler's  Hydrol) 


DISSERTATION 


SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  RE- 
QUIREMENTS FOR  THE  DEGREE  OF  DOCTOR  OF 
PHILOSOPHY  IN  THE  FACULTY  OF  PURE 
SCIENCE  OF  COLUMBIA  UNIVERSITY 

/  ..,. JJII.1T— 


BY 

AARON  RUDERMAN,  B.S.,  M.A, 

1922 


Some  New  Condensations  with  Para 

para-bis  (Dimethylamino)-Benzo- 

hydrol  (Michler's  Hydrol) 


DISSERTATION 


SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  RE- 
QUIREMENTS FOR  THE  DEGREE  OF  DOCTOR  OF 
PHILOSOPHY  IN  THE  FACULTY  OF  PURE 
SCIENCE  OF  COLUMBIA  UNIVERSITY 


BY 

AARON  RUDERMAN,  B.S.,  M.A, 

1922 


TO  THE  MEMORY 

OF 
MY  FATHER 


50208G 


ACKNOWLEDGMENT 

The  author  desires  to  express  his  indebtedness  to  Professor  Marston 
Taylor  Bogert,  who  suggested  this  work  and  under  whose  direction  it  was 
carried  out.  Whatever  merit  this  research  may  have  is  due  to  his  con- 
structive criticism  and  invaluable  assistance. 


SOME    CONDENSATION    REACTIONS    WITH    PARA-PARA-BIS 
(DIMETHYLAMINO)-BENZOHYDROL  (MICHLER'S  HYDROL) 

Introductory 

Fosse1  has  shown  that  ^-substituted  secondary  aromatic  alcohols,  in- 
cluding Michler's  hydrol,  condense  with  one  of  the  methylene  hydrogens 
in  compounds  containing  the  -CO-CH2-CO-  grouping,  with  elimination 
of  a  molecule  of  water  and  the  insertion  of  the  alcohol  residue  in  place  of 
the  hydrogen  removed. 

Inasmuch  as  the  hydrogen  of  the  imino  group  in  imides  of  dibasic  acids 
often  behaves  in  a  way  recalling  that  of  the  hydrogen  in  reactive  methyl- 
enes  similar  to  the  above  (for  example,  compare  the  Gabriel  imide  reac- 
tions with  those  of  malonic  ester),  it  was  thought  of  interest  to  test  this 
experimentally,  particularly  in  view  of  the  fact  that  Mohlau  and  Heinze2 
found  it  impossible  to  effect  such  condensation  with  any  amides  except 
urea,  and  that  Reitzenstein  and  Breuning8  have  reported  that  the  hydrol 
reacts  with  isatin  (an  isomer  of  phthalimide)  by  removal  of  nuclear  and 
not  of  imide  hydrogen.  The  experiments  of  Mohlau  and  his  co-workers4 
have  indicated,  further,  that  the  hydrol  condenses  with  primary  or  second- 
ary aromatic  amines  in  alcoholic  solution  with  formation  of  the  corre- 
sponding leucauramines.  Kern6  and  Noelting,8  using  cone,  sulfuric  acid 

*  Fosse,  Chem.  Zentr.,  1907,  I,  1696;  C.  A.,  2,  823,  2387,  2689  (1908);  Ann.  chim. 
phys.,  [8]  18,  400,  503,531  (1909) '.Bull.  soc.  chim.,  [4]  7,  229  (1910);  Compt.  rend., 
150,  179  (1910);  -4*11.  chim.  phys.,  [9]  13,  118,  154  (1920);  C.  A.,  15,  1711  (1921). 

2  M6hlau  and  Heinze,  Ber.,  35,  359  (1902). 

» Reitzenstein  and  Breuning,  Ann.,  272,  257  (1910). 

«  M6hlau  and  others,  Ber.,  33, 799  (1900) ;  34, 882, 3384  (1901) ;  35,  359  (1902). 

*  Kern,  Ger.  pat.,  27,032,  1883. 

*  Noelting,  Ber.,  24,  3127,  3136,  3139  (1891). 


6 

as  solvent,  noted:  that  the  reaction  then  follows  a  different  course,  nuclear 
hydrogen  being  removed  and  not  that  of  the  amine  groups,  the  products 
being  triphenylmethane  derivatives  and  not  leucauramines.  This  differ- 
ence in  behavior  is  somewhat  akin  to  that  of  benzaldehyde  and  aniline 
which  yield  benzal-aniline  in  alcoholic  solution,  but  diamino-triphenyl- 
methane  in  presence  of  mineral  acid. 

On  dissolving  phthalimide  and  the  hydrol  in  alcohol  and  warming  the 
solution,  a  condensation  product  was  obtained,  crystallizing  in  greenish- 
yellow  plates,  m.  p.  186.7°  (corr.).  This  gave  phthalic  acid  and  leucaur- 
amine  on  hydrolysis  with  dil.  mineral  acid,  and  on  warming  with  dil. 
potassium  hydroxide  solution  added  the  elements  of  water  with  formation' 
of  the  amidic  acid.  Boiling  the  latter  with  dil.  hydrochloric  acid  split 
it  into  phthalic  acid  and  leucauramine. 


C6H/'      N 
NCCK 


(/CO.NRH 
NH+HO.R  — >  C»H4<         >N.R  — 3 


CH 
+  R.NH2    R  =  -CH(CeH4.N(CH,)2)2 

These  facts  justify  the  conclusion  that  the  hydrol  residue  is  in  union 
with  nitrogen  and  not  with  carbon  in  this  product. 

When  cone,  sulfuric  acid  was  substituted  for  alcohol  as  solvent  in  this 
reaction,  and  the  solution  was  warmed  at  100°,  a  colorless  product  was 
obtained  on  precipitation  with  alkali,  which  proved  to  be  a  labile  form 
of  the  compound  (m.  p.  186.7°)  mentioned  above,  and  into  which  it  changed 
slowly  on  standing,  or  more  rapidly  when  heated.  On  dissolving  the  col- 
ored form  in  sulfuric  acid  and  precipitating  rapidly  by  alkali,  a  colorless 
oil  separated  which  soon  congealed  to  the  yellow  form  again. 

Phthalimide  contains  the  2  chromophoric  carbonyl  groups  attached 
to  the  benzene  nucleus  just  as  they  are  arranged  on  one  side  of  the  anthra- 
quinone  formula,  but  with  an  imino  group  on  the  other  side  instead  of  a 
second  benzene  nucleus.  A  similar  relationship  exists  between  the  iso- 
meric  isatin  and  phenanthraquinone.  Phthalimide  is  colorless,  whereas 
isatin  is  a  deep  yellowish-red.  Anthraquinone  is  clear  light  yellow,  but 
phenanthraquinone  is  orange.  The  arrangement  of  the  carbonyl  groups 
in  isatin  is,  therefore,  of  greater  chromophoric  effect  than  that  in 
phthalimide.  Those  auxochromes  which  have  the  most  potent  batho- 
chromic  action  in  the  anthraquinone  group,  NHAryl>NHAlkyl>NH2, 
appear  to  be  the  ones  with  greatest  influence  also  in  the  phthalimide 
molecule,  since  the  amino-phthalic  acid  derivatives  generally  show  decided 
color  (yellow).  Acylation  of  the  amino  group  of  course  discharges  this 
color,  since  the  acylamino  group  is  not  ordinarily  an  auxochrome. 


7 

Kauffmann  and  Beisswenger7  found  that  3-amino-phthalimide  exists 
in  2  tautomeric  forms,  one  yellow  with  green  fluorescence,  and  the  other 
colorless  with  violet  fluorescence.  Such  tautomerism  might  be  explained 
conceivably  by  assuming  a  migration  of  hydrogen  from  the  imino  group 
to  an  adjacent  carbonyl,  giving  a  -C(OH)  :  N-  structure.  Such  an  hy- 
pothesis, however,  scarcely  can  apply  to  the  ^-alkyloxy  phthalanils,  C6H4- 
(CO)2N.C6H4.OR,  which  Pitui  and  Abati8  report  as  also  occurring  in 
colored  (yellow)  and  colorless  modifications,  and  these  investigators, 
recognizing  the  fact,  conclude  that  this  difference  cannot  be  accounted 
for  on  the  basis  of  difference  in  chemical  structure,  but  may  be  due  to  a 
dimorphism  similar  to  that  of  benzophenone. 

Although  but  one  form  of  isatin  is  known,  Pummerer9  has  succeeded 
in  producing  aniline  derivatives  of  the  2  tautomeric  structures, 


XNV 
4^      j>C. 


.NH.C8H6 
(Yellowish  brown)  (Violet) 

If  the  tautomeric  forms  of  phthalyl  leucauramine  observed  by  us  are 
similarly  related  structurally,  the  colorless  modification  would  be  repre- 
sented by  Formula  I,  and  the  colored  by  Formula  II  or  III  — 

O/COv  /C(OHk  /CO 

N.CHR2,CflH4<         >NH:CR2,C6H4<  >N:CR2,C6H4<  >O 

^C<y  ^   CO    '  X::N.CHR« 

I  II  III  IV 

On  the  basis  of  these  structures,  one  would  expect  Formula  I  to  repre- 
sent the  more  stable  (colored),  rather  than  the  less  stable  (colorless) 
tautomer. 

There  remains  the  further  possibility  that  the  colored  form  may  be 
related  to  the  colorless  as  indicated  in  Formulas  I  and  IV.  This  is  a  change 
of  linking  of  the  type  postulated  by  Baly  and  Desch10  in  aceto-acetic  com- 
pounds, and  by  Stewart11  in  ethyl  pyruvate,  a  kind  of  tautomerism  which 
they  have  termed  "isorropesis,"  and  to  which  they  have  attributed  the 
property  of  selective  absorption.  If  then  Formula  IV  is  a  correct  repre- 
sentation of  the  colored  modification,  we  are  dealing  with  a  compound 
possessing  absorption  bands  in  the  visible  part  of  the  spectrum  which  are 
due  to  isorropesis. 

In  favor  of  Formula  IV  it  may  be  remarked  that  it  contains  a  :  C:  N- 
grouping,  resembling  the  chromophore  of  the  Schiff  bases.  On  the  other 
hand,  it  has  been  found  in  the  case  of  the  quinophthalones12  that  the  first 

7  Kauffmann  and  Beisswenger,  Ber.,  36,  2495  (1903). 

8  Pitui  and  Abati,  ibid.,  36,  996  (1903). 

9  Pummerer,  ibid.,  44,  338  (1911). 

10  Baly  and  Desch,  /.  Chem.  Soc.,  87,  766  (1905). 

11  Stewart,  ibid.,  89,  489  (1906). 

«  Eibner  and  others,  Ber.,  35,  2297  (1902);  37,  3008,  3011,  3019  (1904);  etc. 


8 

product  is  the  unsymmetrical  form  V,  which  changes  to  the  symmetrical 
V  at  higher  temperatures,  or  when  treated  with  sodium  ethylate. 


C  rCH.CjHeN 

V  VI 

In  the  formation  of  phthaleins  and  related  types,  phthalic  anhydride  con- 
denses preferably  also  to  unsymmetrical  compounds. 

Finally,  although  phthalimide  itself  exists  in  but  one  form,  to  which  the 
symmetrical  structure  I  is  usually  assigned,  substituted  phthalimides 
are  known  for  which  the  unsymmetrical  form  IV  is  preferred.13 

In  the  case  of  succinimide,  the  condensation  with  the  hydrol  was  carried 
out  only  in  alcoholic  solution,  and  a  succinyl-leucauramine  obtained  which 
was  colorless  when  dry,  but  gave  colored  solutions  (violet  to  blue)  in  alco- 
hol. Hydrolysis  with  dil.  alkali  opened  up  the  imide  to  the  amidic  acid, 
which  was  further  split  by  dil.  acid  into  succinic  acid  and  leucauramine. 

Oxidized  by  lead  dioxide  in  acid  solution,  both  phthalyl-leucauramine 
and  the  corresponding  amidic  acid  gave  carbinols,  the  -CH  grouping 
changing  to  -C(OH)-;  whereas,  with  nitrous  acid,  there  resulted  a  dinitro 
derivative  which  probably  carries  1  nitro  group  adjacent  to  each  of  the 
dimethylamino  groups. 

4-Nitro-phthalimide  did  not  condense  with  the  hydrol,  while  3-amino- 
phthalimide  took  up  2  leucauramine  residues,  1  on  each  nitrogen  atom. 

Both  phthalimidine  and  phthalide  failed  to  react  with  the  hydrol  in 
alcoholic  solution;  but  when  the  phthalide  and  hydrol  were  fused  together, 
the  phthalide  exchanged  both  hydrogens  of  its  methylene  group  for  leuc- 
auramine radicals,  giving  a  product  which  probably  possesses  the  struc- 

ture O.CO.C6H4.C(CHR2)2,  and  is  colored  (pink)  in  acid  solution,  but 
is  colorless  in  alkali.  The  behavior  of  the  phthalimidine  was  quite  un- 
expected, since  it  contains  the  methylene  group  of  phthalide  and  the 
imino  of  phthalimide. 

Saccharin,  which  differs  from  phthalimide  only  in  containing  an  SOi 
group  in  place  of  one  of  the  carbonyl  groups  of  the  latter,  seems  to  react 
with  the  hydrol  only  to  the  extent  of  salt  formation,  since  the  addition  of 
either  one  to  a  dil.  alcoholic  solution  of  the  other  gives  immediately  a 
deep  blue  color,  and  in  fact  this  may  be  used  as  a  delicate  test  for  the 
presence  of  small  amounts  of  saccharin. 

Dehydrothio-£-toluidine  condenses  smoothly  with  1  mole  of  the  hydrol 
in  alcoholic  solution. 

Mohlau  and  Klopper14  observed  that  2  moles  of  hydrol  united  with  1 

13  Hoogewerf  and  v.  Dorp,  Rec.  trav.  chim.,  13,  93  (1894).     v.  d.  Meulen,  ibid.,  15, 
286,  323  (1896);  etc. 

14  Mohlau  and  Klopper,  Ber.,  32,  2146  (1899). 


of  benzoquinone  (with  elimination  of  2  moles  of  water),  whereas  with 
a-naphthoquinone  the  union  occurred  with  equal  moles.  In  the  case  of 
/3-naphthoquinone,  and  of  phenanthraquinone,  no  condensation  took 
place.  They  concluded,  therefore,  that  £-quinones  condense  with  the 
hydrol,  but  0-quinones  do  not.  Our  own  experiments  do  not  bear  out 
this  conclusion,  for  we  have  tried  in  vain  to  cause  the  hydrol  to  react 
with  anthraquinone  in  either  alcohol  or  cone,  sulfuric  acid;  nor  would 
alizarin  react  in  the  latter  solvent  at  100°,  although  under  similar  condi- 
tions, the  hydrol  condenses  readily  with  phenols  and  phenolic  ethers;11  a- 
and  |8-amino-anthraquinones  were  equally  unreactive  in  alcoholic  solution. 
Mohlau  and  Heinze2  state  that  their  attempts  to  condense  the  hydrol 
with  acid  amides  were  unsuccessful,  except  in  the  case  of  urea,  which  united 
with  2  moles  of  this  secondary  alcohol,  We  have  found,  further,  that 
negative  results  are  obtained  also  with  thio-urea  and  with  the  cyclic  ben- 
zoylene-urea  (2,4-dihydroxy-quinazoline) . 

Experimental 

Michler's  hydrol  was  prepared  by  oxidizing  the  corresponding  bis(-dimethylamino)- 
diphenylmethane  with  lead  dioxide,  as  recommended  by  Mohlau  and  Heinze;2  yield  of 
crude  product,  85%.  To  avoid  formation  of  large  amounts  of  tar  in  the  recrystallization 
of  this  crude  material,  it  was  found  advantageous  to  dissolve  about  150  g.  in  a  liter  of 
gasolene  previously  warmed  to  80-85°,  and  then  allow  the  solution  to  cool.  Instead  of 
gasolene,  benzene  may  be  employed  at  the  same  temperature,  but  with  double  the  con- 
centration of  hydrol.  The  melting  point  of  the  purified  product  varied  for  different  lots 
from  96-98°  (uncorr.) .  The  figures  given  in  the  literature  run  from  96  °  to  102  °. 

Production  of  the  hydrol  by  the  action  of  sodium  amalgam  upon  an  alcoholic  solu- 
tion of  the  ketone2  proved  unsatisfactory,  because  of  the  frequent  incompleteness  of  the 
reduction  and  consequent  difficulties  of  purification. 

The  lead  dioxide  employed  was  precipitated  by  adding  a  solution  of  bleaching 
powder  to  one  of  lead  acetate,  and  was  standardized  by  titration  with  sodium  thiosulfate 
in  presence  of  a  dil.  acetic  acid  solution  of  potassium  iodide. 

Succinyl-leucauramine,  ((CH3)2N.C6H4)sCH.N.CO.CH2.CH2.CO.— A  solution  of 
5  g.  of  succinimide  (1  mole)  and  13  g.  (1  mole)  of  hydrol  in  200  cc.  of  alcohol  was  boiled 
gently  for  10  hours.  On  cooling,  a  few  crystals  of  the  condensation  product  separated. 
More  were  recovered  on  concentration.  Recrystallized  from  alcohol,  the  substance  was 
obtained  in  nearly  colorless  minute  needles,  melting  at  151°  fcorr.),  which  darkened  on 
standing;  yield,  approximately  50%.  It  is  soluble  also  in  hot  methyl  alcohol  or  hot 
benzene. 

Analyses.     Calc.  for  C21H25O2N8:   N,  11.96.     Found:    12.09,  12.22. 

Succmyl-dinitro-leucauramine,  prepared  from  the  above  by  the  action  of  nitrous 
acid,  in  the  same  way  as  the  corresponding  phthalimide  derivative  described  beyond, 
crystallized  from  alcohol  as  a  yellowish-brown  powder,  melting  with  decomposition 
at  94°  to  96°;  yield,  about  90%. 

Analyses.     Calc.  for  C21H2SOaN6:   N,  15.87.     Found:    15.61,  15.95. 

p,p '-Bis (dimethylammo)-benzohydryl-succinamidic  Acid,  ((CH8)«N.C«H<)2CH.NH.- 
CO.CH2.CH2.COOH.— Five  g.  of  succinyl-leucauramine  was  warmed  for  2  hours  at  100° 

»  Ger.  pats.,  58,483,  64,217,  64,306,  66,072,  67,429,  72,898,  76,931,  79,320. 


10 

with  10  cc.  of  a  dilute  ("about  10%)  potassium  hydroxide  solution,  but  a  clear  solution 
was  not  obtained.  Water  (300  cc.)  was  added,  therefore,  the  mixture  boiled,  filtered, 
the  filtrate  neutralized  with  dil.  acid  and  worked  up  as  described  beyond  for  the  anal- 
ogous phthalamidic  compound.  The  crude  product  was  crystallized  from  water  contain- 
ing 10  to  15%  of  alcohol,  and  minute  colorless  needles  were  obtained.  These  melted  at 
170°,  and  on  standing  gradually  assumed  a  pale  slaty  color. 

Analyses.     Calc.  for  CziH^OsNs:   N,  11.39.     Found:    11.14,  11.30. 


Phthalyl-leucauramine,  ((CHa^N.CeH^CH.N.CO.C^.CO.— The  requisite  phthal- 
imide  was  prepared  by  the  method  of  Dunlap,18  by  fusing  a  mixture  of  equimolar 
amounts  of  phthalic  anhydride  and  urea,  and  was  obtained  in  a  yield  of  97%;  m.  p., 
233.5°  fcorr.). 

A  solution  of  10  g.  of  phthalimide  (1  mole)  and  18  g.  ( 1  mole)  of  the  hydrol,  in  300  cc. 
of  alcohol,  was  boiled  gently  for  10  hours,  and  then  cooled.  Seventeen  g.  of  greenish- 
yellow  leaflets  separated  from  the  cold  solution,  and  4  g.  more  was  recovered  by  con- 
centrating the  mother  liquor,  making  the  total  yield  80%.  The  purified  compound 
melted  at  186.7°  (corr.),  and  crystallized  in  greenish-yellow  prisms  or  leaflets. 

Analyses.  Calc.  for  C^H^N,:  C,  75.18;  H,  6.27;  N,  10.52.  Found:  C,  74.88, 
75.30;  H,  6.21,  6.36;  N,  10.70,  10.70. 

The  substance  is  soluble  in  cold  acetone,  difficultly  soluble  in  ether  or  ligroin,  and 
dissolves  in  alcohol,  ethyl  acetate,  carbon  disulfide,  or  benzene,  at  their  boiling-points. 
As  phthalimide  is  difficultly  soluble  in  either  carbon  disulfide  or  benzene,  it  may  be 
separated  thus  from  its  hydrol  condensation  product.  When  dry  hydrogen  chloride  is 
passed  into  an  anhydrous  ether  solution  of  the  new  compound,  a  greenish  precipitate 
separates  which  is  probably  the  mono-hydrochloride.  On  further  addition  of  hydrogen 
chloride,  this  precipitate  loses  its  color,  presumably  through  formation  of  the  di-hydro- 
chloride.  The  latter  dissolves  in  water  to  form  a  green  solution  of  the  same  color  as 
given  by  the  original  phthalyl-leucauramine  when  dissolved  in  dil.  hydrochloric  acid. 

When  cone,  sulfuric  acid  was  substituted  for  the  alcohol  in  the  above  reaction  and 
the  solution  was  warmed  at  100°  for  several  hours  and  then  cooled,  a  colorless  product 
separated  on  neutralization  with  alkali,  which  proved  to  be  a  labile  form  of  the  compound 
obtained  from  alcoholic  solution.  Yield,  about  18-20%.  It  dissolves  more  readily  than 
the  stable  form  in  alcohol,  acetone  or  benzene.  After  long  standing  in  alcoholic  solution, 
greenish-yellow  crystals  of  the  stable  form  separate.  The  same  change  ensues  slowly 
when  the  dry  substance  is  left  in  the  open;  heat  accelerates  the  transformation.  When 
the  colorless  modification  was  heated,  it  melted  at  about  90°,  changed  to  the  greenish- 
yellow  form  and  resolidified.  This  resolidified  product,  crystallized  from  alcohol, 
showed  the  correct  melting  point  (186.7°)  for  the  stable  form.  When  it  was  dissolved 
in  cone,  sulfuric  acid,  or  even  in  the  dil.  acid,  a  colorless  or  but  faintly  colored  solution 
resulted,  from  which  rapid  addition  of  alkali  precipitated  a  colorless  oil.  This 
oil  congealed  to  a  yellow  solid,  which  gradually  assumed  the  greenish-yellow  characteris- 
tic of  the  stable  form. 


Phthalyl-leucauramine  Carbinol,  ((CH3)2N.C6H4)2C(OH) .N.CO.C6H4.CO.— Twenty 
g.  of  phthalyl-leucauramine  was  dissolved  in  a  mixture  of  160  cc.  of  water  and  12  cc.  of 
cone,  hydrochloric  acid,  and  1  liter  of  water  and  10  cc.  of  glacial  acetic  acid  were  added. 
The  mixture  was  stirred  vigorously  while  30  g.  of  40%  lead  dioxide  paste,  in  about  150 
cc.  of  water,  was  added  gradually.  The  stirring  was  continued  for  an  hour  longer,  when 
a  solution  of  16  g.  of  sodium  sulfate  was  poured  in,  to  remove  the  lead.  On  making 
the  filtrate  alkaline,  only  a  small  amount  of  precipitate  was  formed.  The  lead  sulfate 

16  Dunlap,  /.  Am.  Chem.  Soc.,  18,  333  (1896). 


11, 

precipitate,  therefore,  was  boiled  with  dil.  hydrochloric  acid  (50  cc.  of  cone,  acid  to  300 
cc.  of  water),  and  the  mixture  filtered  hot.  As  the  solution  cooled  some  lead  sulfate 
crystallized  and  was  removed.  The  filtrate  from  this  was  precipitated  with  dil. 
sodium  hydroxide  solution,  and  the  carbinol  extracted  from  this  precipitate  by  hot  al- 
cohol. It  was  recrystallized  from  either  alcohol  or  acetone,  and  dissolved  also  in  chloro- 
form, but  not  appreciably  in  ether.  It  formed  nearly  colorless  crystals,  melting  at  176  * 
(corr.);  yield,  60%. 

Analyses.     Calc.  for  C25H25O3N3:  N,  10.11.    Found:   10.34,  10.23. 

Dmitro-phthalyl-leucauramine. — Five  g.  of  phthalyl-leucauramine  was  dissolved 
in  30  cc.  of  dil.  (1:1)  hydrochloric  acid,  and  an  aqueous  solution  of  sodium  nitrite  (4 
moles)  run  in  slowly  as  long  as  it  caused  the  separation  of  precipitate.  The  nitrite 
must  be  added  very  carefully,  so  that  the  temperature  does  not  rise  to  the  point  where 
excessive  formation  of  nitrogen  oxides  occurs,  or  the  yield  of  nitro  derivative  will  be 
diminished.  The  brown  precipitate  was  collected  and  crystallized  from  alcohol,  or  from 
glacial  acetic  acid,  and  then  appeared  as  a  yellowish-brown  solid,  melting  with  decompo- 
sition at  104°;  yield,  90%.  It  gave  no  Liebermann  reaction  for  nitroso  groups,  and  was 
free  from  halogen. 

Analyses.     Calc.  for  C26H23O6N6:  N,  14.32.     Found:   14.08,14.02. 

An  effort  to  secure  the  same  product  was  made  by  dissolving  the  phthalyl-leucauram- 
ine in  cone,  sulfuric  acid,  adding  a  mixture  of  cone,  sulfuric  and  cone,  nitric  acids  at 
— 5  °  to  0  °,  and  finally  pouring  the  mixture  into  ice  water.  Some  phthalimide  separated, 
but  saturation  of  the  nitrate  with  sodium  carbonate  precipitated  only  unchanged  initial 
material. 

Reduction  of  the  dinitro  derivative  with  tin  and  hydrochloric  acid  yielded  brown 
oils  difficult  to  handle,  which  were  not  further  investigated. 

0,0'-Dinitro-/>,£'-bis(dimethylamino)  diphenylmethane  was  prepared  according  to 
the  directions  of  Pinnow17  in  a  yield  of  86%;  it  melted  at  188°  (uncorr.);  Pinnow  gives 
191.5°.  Twenty  g.  of  this  product  was  suspended  in  600  cc.  of  water  and  sufficient 
hydrochloric  acid  added  to  give  a  clear  solution.  Twenty-six  g.  of  lead  dioxide  paste 
(40%),  mixed  with  100  cc.  of  water,  was  stirred  in  and  the  oxidation  continued  for  an 
hour  at  laboratory  temperature;  the  mixture  was  then  heated  to  60°  to  complete  the 
reaction,  and  on  dilution  with  water,  the  original  diphenylmethane  compound  separated 
unaltered.  In  view  of  this  result,  it  seemed  profitless  to  attempt  the  oxidation  of 
the  dinitro-phthalyl-leucauramine. 

^,/?'-Bis(dimethylamino)-benzohydryl-phthalamidicAcid,  ((CH3)2N.C«H4)jCH.NH.- 
CO.C6H4.COOH. — Fifty  g.  (1  mole)  of  phthalyl-leucauramine  was  covered  with  50  cc.  of 
a  dil.  (about  10%)  aqueous  potassium  hydroxide  solution  (slightly  over  1  mole),  and 
the  mixture  heated  at  100°  for  about  half  an  hour,  at  the  end  of  which  time  the  solid  was 
nearly  all  dissolved.  Longer  heating  caused  evolution  of  ammonia,  due  probably  to 
the  separation  of  leucauramine  and  the  hydrolysis  of  the  latter  to  hydrol  and  ammonia. 
Water  was  added  to  the  alkaline  solution  and  then  dil.  sulfuric  acid  to  neutralization.  As 
the  precipitate  formed  was  soluble  either  in  acid  or  alkali,  it  was  found  advisable  not 
to  overrun  the  neutral  point.  This  point  was  easily  detected  by  the  sudden  change  in 
color.  The  colorless  precipitate  dissolved  readily  in  methyl  or  ethyl  alcohol,  chloro- 
form or  acetone,  but  proved  very  difficultly  soluble  in  carbon  tetrachloride  or  gasolene. 
On  recrystallization  from  alcohol,  colorless  needles  were  obtained,  which  melted  with 
decomposition  at  163.8°  (corr.);  yield,  90%. 

Analyses.     Calc.  for  CKH27O^3:  N,  10.07.     Found:   10.03,10.14. 

Some  of  this  amidic  acid  was  dissolved  in  dil.  hydrochloric  acid  and  the  solution 

»  Pinnow,  Ber.,  27,  3161  (1894). 


12 

heated  at  100°  for  an  hour.  The  solution  was  then  diluted  and  cooled.  Phthalic  acid 
separated  and  was  filtered  out.  The  filtrate  was  then  made  alkaline  and  leucauramine 
precipitated.  Similar  results  were  secured  when  the  original  phthalyl-leucauramine  was 
saponified  with  dil.  (20%)  hydrochloric  acid  at  100°,  without  separation  of  the  inter- 
mediate amidic  acid. 

Oxidation  of  the  Amidic  Acid. — Five  g.  (1  mole)  of  the  amidic  acid  was  dissolved 
in  40  cc.  of  water  and  3  cc.  of  cone,  hydrochloric  acid,  and  a  solution  of  5  cc.  of  glacial 
acetic  acid  in  200  cc.  of  water  poured  in.  This  solution  was  stirred  vigorously  while 
6  g.  (1  mole)  of  lead  dioxide  paste  (40%),  suspended  in  50  cc.  of  water,  was  added  slowly. 
The  stirring  was  continued  for  half  an  hour  longer,  and  the  lead  then  precipitated  by 
dil.  sulfuric  acid.  The  lead  sulfate  was  removed  and  washed  with  dil.  hydrochloric  acid, 
the  washings  being  combined  with  the  original  filtrate.  The  united  filtrate  and  washings 
were  made  alkaline,  and  the  desired  carbinol  thereby  precipitated.  It  was  purified  by 
crystallization  from  dil.  acetone,  and  then  formed  a  brownish  solid,  melting  at  187° 
(corr.),  and  soluble  also  in  alcohol;  yield,  75%. 

Analyses.  Calc.  for  ((CH,),N.C«H4)2C(OH).NH.CO.C6H4.COOH:  N,  9.70. 
Found:  9.48,  9.75. 

Michler's  Hydrol  and  Phthalimidine. — The  phthalimidine  was  prepared  from 
phthalimide  in  the  usual  way,18  and  melted  at  150°  (uncorr.).  Five  g.  (1  mole)  of  this 
imidine  and  30.5  g.  (3  moles)  of  the  hydrol  were  heated  with  250  cc.  of  alcohol  and  a 
few  drops  of  glacial  acetic  acid  for  a  day  at  100°,  but  no  condensation  occurred  and  the 
initial  materials  were  recovered  unchanged. 


Di-bis(dunethylammo)-benzohydryl-phthalide, 
— Phthalide  and  the  hydrol  were  mixed  in  the  proportion  of  one  mole  of  the  former  to  two 
of  the  latter,  a  few  drops  of  glacial  acetic  added,  and  the  mixture  was  heated  at  100°  for 
6  to  8  hours,  giving  a  blue,  pasty  mass  which  solidified  on  cooling.  This  solid  was  pul- 
verized and  extracted  with  boiling  alcohol,  to  recover  unchanged  phthalide  and  hydrol. 
The  insoluble  residue  was  crystallized  from  a  mixture  of  1  part  of  gasolene  and  2 
parts  of  xylene,  and  then  formed  reddish-brown  prismatic  crystals,  melting  at  201  ° 
(corr.),  which  were  but  slightly  soluble  in  alcohol,  ethyl  acetate,  acetone,  carbon  tetra- 
chloride,  benzene,  aniline  or  gasolene,  and  somewhat  more  soluble  in  hot  xylene;  yield, 
about  10%.  The  same  compound  resulted  when  the  phthalide  and  hydrol  were  present 
in  equimolar  proportions,  and  no  monobenzohydryl  derivative  was  encountered. 

Analyses.  Calc.  for  C^HUeO^:  C,  78.99;  H,  7.30;  N,  8.77.  Found:  C,  78.84, 
78.63;  H,  7.32,  7.20;  N,  8.79,  8.85. 

With  acids,  the  compound  turns  pink;  but  the  color  is  discharged  on  addition  of 
alkali,  and  the  freshly  separated  compound  is  practically  colorless.  In  alcoholic  solution, 
the  phthalide  and  hydrol  do  not  interact  at  the  boiling  point  of  the  mixture.  The 
phthalide  used  in  these  experiments  was  prepared  by  hydrolysis  of  nitroso-phthalimi- 
dine,18  and  melted  at  73°  (corr.). 

Michler's  Hydrol  and  4-Nitro-phthalimide. — Equimolar  amounts  of  the  two  were 
dissolved  in  alcohol  and  the  solution  boiled  for  10  hours  on  a  steam-bath.  The  solution 
turned  blue,  but  the  hydrol  and  imide  were  recovered  from  the  solution  unaltered. 

3-Leucauraminyl-phthalyl-leucauramine,  ( (CHs^N.QH^CH.NH.CeHgfCO^N.- 
CH(C6H4.N(CH3)2)2.— 0.87  g.  (1  mole)  of  3-amino-phthalimide  and  3  g.  (2  moles) 
of  hydrol  were  dissolved  in  35  cc.  of  alcohol  containing  a  few  drops  of  glacial  acetic 
acid,  and  the  solution  boiled  gently  for  10  hours.  As  the  mixture  cooled,  a  small 
amount  of  tar  separated,  and  more  began  to  come  out  on  further  concentration.  The 

18  Graebe.  Ann.,  247,  291  (1888);  Ber.,  17,  2598  (1884). 


13. 

alcoholic  solution,  therefore,  was  treated  with  dil.  hydrochloric  acid,  and  the  clear  sol- 
ution precipitated  by  neutralization  with  alkali.  The  dried  precipitate  amounted  to 
3  g.  Boiling  with  alcohol  appeared  to  decompose  it  slowly  with  formation  of  tar,  as 
noted  above,  but  crystallization  from  acetone  yielded  greenish-yellow  plates,  melting 
at  219-220°  (corr.),  analysis  of  which  showed  that  both  the  amino  and  the  imide  groups 
had  reacted  with  the  hydrol. 

Analyses.  Calc.  for  C^H^CWe:  C,  75.78;  H,  6.77.  Found:  C,  75.61,  76.09; 
H,  7.05,  7.11. 

The  product  is  difficultly  soluble  in  petroleum  ether,  but  rather  readily  soluble  in 
benzene,  and  a  mixture  of  the  two  may  be  used  as  a  crystallizing  medium,  but  is  not  so 
satisfactory  as  acetone.  Its  solutions  are  not  fluorescent,  although  those  of  the  initial 
amino-phthalimide  are.  The  pale  color  of  the  solid  substance  is  also  noteworthy,  and 
is  in  harmony  with  its  leucauramine  structure. 

Michler's  Hydrol  and  Saccharin  yielded  no  condensation  product  when  the  two 
were  heated  together  in  equimolar  proportion  in  alcoholic  solution,  with  or  without 
the  addition  of  small  amounts  of  glacial  acetic  acid.  It  was  observed,  however,  that 
when  the  two  substances  were  brought  together  even  in  very  dilute  alcoholic  solution, 
a  deep  blue  color  resulted,  presumably  due  to  the  formation  of  a  quinoid  salt  of  the  hy- 
drol, and  this  reaction  appears  to  be  a  delicate  test  for  either  compound.  The  color  is 
discharged  by  sulfur  dioxide  and  restored  by  addition  of  the  component  originally  present 
in  the  smaller  amount.  The  corresponding  ketone  (Michler's  ketone)  and  hydrocarbon 
give  no  such  color  reaction  when  saccharin  is  added  to  their  alcoholic  solutions. 

Michler's  Hydrol  and  Anthraquinone. — No  condensation  was  effected  either  in 
alcoholic  solution  or  in  cone,  sulfuric  acid. 

Michler's  Hydrol  and  Alizarin. — In  cone,  sulfuric  acid  solution,  no  condensation 
occurred. 

Michler's  Hydrol  and  Amino-anthraquinones. — The  condensation  was  attempted 
in  alcoholic  solution,  with  both  a-  and  /3-amino-anthraquinone,  and  failed  in  both 
cases. 

Michler's  Hydrol  and  Thio-urea. — Mohlau  and  Heinze,*  report  that  the  hydrol 
condenses  in  alcoholic  solution  with  urea,  but  our  experiments  with  thio-urea  were 
less  successful.  We  dissolved  2  moles  of  the  hydrol  and  1  mole  of  thio-urea  in  alcohol, 
and  boiled  the  solution  gently  for  8  hours.  There  was  no  indication  of  any  change,  so 
more  thio-urea  (3  moles)  was  added  and  the  boiling  resumed,  but  we  failed  to  accomplish 
any  condensation. 

Michler's  Hydrol  and  Benzoylene-urea  did  not  condense  in  alcoholic  solution. 

/S 
p,p'-Bis  (dimethylamino) -benzohydryl-dehydrothio-^-toluidine,  CH3 .  C«Hjj<^ 

C6H4.NH.CH(C6H4.N(CHs)2)2.— Five  g.  (1  mole)  of  dehydrothio-£-toluidine  and  5.5 
g.  (1  mole)  of  the  hydrol  were  dissolved  in  250  cc.  of  alcohol  and  the  solution  was  boiled 
gently  on  the  steam-bath.  The  original  blue  color  of  the  solution  was  almost  completely 
discharged  after  a  half  hour's  boiling  and  a  faint  fluorescence  appeared,  while  a  straw- 
yellow  precipitate  separated  from  the  hot  solution,  the  amount  increasing  as  the  boiling 
was  continued.  When  this  precipitate  no  longer  increased  in  amount,  the  solution  was 
cooled  and  filtered,  and  a  further  crop  of  crystals  recovered  by  concentration  of  the 
mother  liquor.  The  crude  product  was  purified  by  crystallization  from  benzene,  washed 
with  acetone,  to  remove  any  adhering  dehydrothio-/>-toluidine,  and  then  appeared  as  a 
pale  yellow  micro-crystalline  solid,  melting  at  190-191°  (corr.),  moderately  soluble  in 
alcohol  or  in  benzene,  and  difficultly  soluble  in  acetone  or  ether;  yield,  75%. 

Analyses.     Calc.  for  CMHMN4S:  C,  75.60;  H,  6.50.    Found:  C,  75.94 ;  H,  6.55. 


14 

Summary 

1.  £,£'-Bis(dimethylamino)-benzohydrol,  better  known  as  Michler's 
hydrol,  condenses  with  the  imides  of  succinic  and  phthalic  acids  to  suc- 
cinyl-  and  phthalyl-leucauramines,  which  can  be  hydrolyzed  by  alkali  to 
the  corresponding  amidic  acids.     The  results  of  the  condensation  were 
the  same  whether  carried  out  in  cone,  sulfuric  acid  or  in  alcoholic  solution. 

2.  Phthalyl-leucauramine  exists  in  a  labile,  colorless  (m.  p.  90°),  and 
a  stable,  greenish-yellow,  modification  (m.  p.  186.7°),  which  are  inter- 
convertible. 

3.  These  acyl  leucauramines  yield  the  corresponding  carbinols  when 
oxidized  by  lead  dioxide,  or  give  dinitro  derivatives  when  treated  with 
nitrous  acid. 

4.  Phthalimidine  and  the  hydrol  do  not  condense  in  alcoholic  solution. 

5.  Phthalide  reacts  with  two  moles  of  the  hydrol. 

6.  3-Amino-phthalimide  also  condenses  with  2  moles  of  hydrol,  one 
entering  the  amino  and  the  other  the  imide  group.     4-Nitro-phthalimide, 
on  the  other  hand,  does  not  react. 

7.  The  hydrol  is  a  delicate  reagent  for  detecting  saccharin  in  alcoholic 
solution,  giving  a  deep  blue  coloration  even  in  dilute  solutions. 

8.  Dehydrothio-^-toluidine  condenses  readily  with  the  hydrol  in  alco- 
holic solution. 

9.  Anthraquinone,  its  a-  or  0-amino  derivative,  alizarin,  thio-urea  or 
benzoylene-urea,  fails  to  react  with  the  hydrol,  under  the  conditions  of 
our  experiments. 


BIBLIOGRAPHY  OF  MICHLER'S  HYDROL 
1876— Michler-Dupertuis,  Ber.,  9,  1899;  Ann.,  184,  174. 
1883— Kern,  D.  R.  P.  27,032;  FrdL,  [1]  76. 
1884— Badische,  Ber.,  17R,  244. 
1887— Myer,  Ber.,  20,  1733. 

1889— Nathansohn-Miller,  Ber.,  22,  1879;  D.  R.  P.  54,113. 
1890— Bayer,  D.  R.  P.  58,483,  67,429,  58,969,  60,606;  Badische,  D.  R.  P.  58,198,  58,277- 

Einhorn,  D.  R.  P.  69,  554. 
1891— Nolting,  Ber.,  24,  553,  3127,  3136,  3139;  Bayer,  Ber.,  24R,  873,  926;  Bayer, 

D.  R.  P.  66,072,  63,743,  64,306,  68,291,  69,654,  66,712;  Badische,  D.  R.  P.  64,217. 
1892— Bayer,  Ber.,  25R,  356,  836,  885;  Bayer,  D.  R.  P.  67,434,  69,948,  72,898,  68,865, 

67,232,  68,381,  73,112,  76,073,  80,510. 
1893— Bayer,  Ber.,  26R,  259,  464,  562,  563,  631,  632,  633,  916,  920;  Bayer,  D.  R.  P. 

80,669,  80,282;  Einhorn,  Ber.,  26R,  849;  Rosenthiel,  Bull.   [3]  9,  127;  Weil, 

D.  R.  P.  75,334;  Badische,  D.  R.  P.  70,908,  76,931  ;Add.,  5534,  5540. 
1894— Weil,  Ber.,  27,  1408,  3316,  R825;  Bayer,   Ber.,  27R,  355,  912;  Bayer,  D.  R.  P. 

81,374,  79,250,  82,268,  82,270,  82,634,  80,510/90,881,  82,570;  Badische,  D.  R.  P. 

79,320;  Badische,  Ber.,  27R,  960;  Geigy,  D.  R.  P.  80,982;  Rosenthiel,  Bull, 

[3]  11,  405. 
1895— Bayer,  Ber.,  28R,  585,  705,  880;  Geigy,  D.  R.  P.  87,176;  Badisch?  D.  R.  P. 

85,199;  Rosenthiel,  Bull,  [3]  13,  275. 
1896— Fritsch,  Ber.,  29,  2300;  Badische,  Ber.,  29R,  317;  Geigy,  Geigy,  Ber.,  29R,  715; 

Bayer,  D.  R.  P.  90,881;  97,106;  Bayer,  Ber.,  29R,  705;  Meister-Lucius-Bruning, 

D.  R.  P.  96,230. 
1897— Hinsbeig,  Ber.,  30,  2803;  Suais,  Bull,  [3]  17,  517;  Bayer,  D.  R.  P.  97,286,  98,546; 

Meister-Lucius-Bruning,  D.  R.  P.  97,638;  97,822;  98,012. 
1898— Klager-Allensdorff,  Ber.,  31,  1002;  Mohlau,  Ber.,  31,  2351;  Vidal-Haas,  D.  R.  P. 

106,721,  116,352,  116,566;  Lucius-Bruning,  D.  R.  P.  108,129,  110,086. 
1899— Mohlau-Klopfer,  Ber.,  32,  2146;  Aktien-Gesellschaft,  D.  R.  P.  109,664, 112,175; 

Add.,  6450;  Lucius-Bruning,  D.  R.  P.  111,506 
1900— Hantzsch-Osswald,  Ber.,  33, 283;  Mohlau-Schaposchnikoff,  Ber.,  33, 799;  Mohlau- 

Kegel,  Ber.,  33,  2860;  Bayer,  D.  R.  P.  125,580. 
1901— Mohlau-Heinze,  Ber.,  34,  882;  Escherich-Moest,  D.  R.  P.  133,896;  Add.,  8316, 

7664;  Leonhardt,  D.  R.  P.  12,806;  Mohlau-Gralert,  Ber.,  34,  3384. 
1902— Mohlau-Heinze,  Ber.,  35,  359,  376;  Casein,  D.  R.  P.  149,322,  148,031,  144,536; 

Fischer- Weiss,    Centralblatt,    [1]  471;  Guyot-Granderye,   Centralblatt,    [1]  873; 

Elbs-Brand,  Centralblatt,  [2]  1199. 

1903— Ehrlich-Sachs,  Ber.,  36, 4298;  Fritsch,  Centralblatt,  [2]  1440. 
1904— Nolting,  Ber.,  37,  1908;  Lucius-Bruning,  D.  R.  P.  166,308;  167,348,  168,080; 

Merck,  D.  R.  P.  167,462,  167,463. 
1905— Aktien-Gesellschaft,   D.   R.   P.    171,684;  Reitzenstein-Runge,    Centralblatt,    [1] 

1020. 
1906— Nolting-Gerlinger,  Ber.,  39,  2053;  Reitzenstein-Rotschild,  Centralblatt,  [1]  1168; 

Fosse,  Bull,  [3]  35,  1005. 
1907— Reitzenstein-Schwerdt,    Centralblatt,    [2]    1413;   Badische,   D.   R.   P.    186,889; 

Volocek-Jelinek,  Ber.,  40,  408;  Fosse,  Centralblatt,  [1]  1696;  Geigy,  Centralblatt, 

[1]  776;  Bayer,  Centralblatt,  [2]  988. 
1908— Fosse,  Chem.  Abstr.,  823,  2387,  2689;  Mohlau,  Ber.,  41,  989;  Auwers-Eisenchlor, 

Centralblatt,    [1]    1048;    Bielki-Koloniew,    Centralblatt,    [2]    877;    Gyot-Pignet, 

Centralblatt,  [2]  51. 
1909— Fosse,  Ann.  Chim.  Phys.,  [8]  18,  400,  503,  531;  Votocek-Kranz,  Ber.,  42,  1602. 


1910— Sudborogh-Beard,  Chem.  Abstr.,  2116;  Fosse,  Bull.,   [4]  7,  229;  Compt.  rend., 

150,   179;   Reitzenstein-Breuning,   Ann.,   372,  263;   Marschalek-Nicolajewsky, 

Ber.,  43,  1701. 
1912— Villiger-Kopetschni,   Ber.,   45,   2910;   Reitzenstein-Bonitsch,    J.   Prak.    Chem., 

[2]  86, 38,  61,  66;  Brit.  P.  3134;  Schmidlein-Lang,  Ber.,  45,  908;  D.  R.  P.  250,366; 

Chem.  Abstr.,  3531;  Kyot-Kovache,  Compt.  rend.,  155,  838. 
1913— Gyot-Kovache,  Compt.  rend.,  156,  1326;  Centralblatt,  [2]  45;  Straus-Zeime,  Ber., 

46,  2269;  Votocek-Kohler,  Ber.,  46,   1763;  Braun-Koscielski,  Ber.,  46,   1528; 

Green,  J.  C.  S.,  103,  927;  Fischl,  Monats.,  34, 337,  342  note. 
1914— Esseln-Clarke,  Centralblatt,  [1]  1277. 

1917— Montagne,  Chem.  Weekblad,  13,  1246,  1966;  Ber.,  49,  2243;  Chem.  Abst.,  586. 
1918— Kovoche,  Ann.  Chim.  Phys.,  [9]  10,  184. 

1919— Kovache,  Rev.  Gen.  de  materies  colorantes,  etc.,  23,  25;  Centralblatt,  [1]  1022. 
1920— Fosse,  Ann.  Chim.  Phys.,  [9]  13,  118,  154;  Chem.  Abstr.,  1963. 
1921— Fosse,  Chem.  Abstr.,  1711. 


VITA 

Aaron  Ruderman  was  born  May  21,  1895.  After  a  preliminary  educa- 
tion in  the  schools  of  New  York  City  he  entered  the  College  of  the  City 
of  New  York  in  1915.  In  May  1918  he  entered  the  Chemical  Warfare 
Service,  U.  S.  A.  and  was  assigned  to  U.  S.  Bureau  of  Standards.  After 
his  discharge  from  the  army  he  was  awarded  the  degree  of  B.S.  in  Feb. 
1919.  Since  then  he  pursued  graduate  studies  at  Columbia  University 
under  the  faculty  of  pure  science.  He  received  the  degree  of  M.A.  in  1920. 


Photomount 
Pamphlet 

Binder 
Gaylord  Bros. 

Makers 
Syracuse,  N.  Y. 

PAT.  JAN  21,  1908 


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